DESCRIPTION: This project is focused on genetic and biochemical studies designed to test the role of FEN-1 in trinucleotide repeat expansion. One set of goals is to examine the role of FEN-1 in trinucleotide repeat expansion using mouse models. Alterations in a variety of micro satellite loci including large trinucleotide transgenes will be studied using single molecule analysis of DNA from somatic and germline tissues. Another collection of goals is to test a specific model for how inhibition of FEN-1 activity can lead to expansion mutations as a consequence of alterations in its role in the processing of Okazaki fragments. The biochemical properties of FEN1 and additional Okazaki fragment processing enzymes including PCNA, RNAse H1 and ligase I will be studied to assess their potential roles in genetic instability.